Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor
Open accessAbstract
Stress Protector: During prolonged fasting, the oxidation of fatty acids leads to increased accumulation of d -β-hydroxybutyrate (βOHB) in the bloodstream. Such increased concentrations of βOHB inhibit class I histone deacetylases. Histone acetylation in turn influences transcriptional activity at various genes. Shimazu et al. (p. 211 , published online 6 December; see the Perspective by Sassone-Corsi ) found that among the genes showing increased transcription in animals treated with high concentrations of βOHB were two genes implicated in cellular responses to oxidative stress. When treated ahead of time with βOHB, mice were protected from the toxic effects of the oxidative stress causing poison paraquat.
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BHB acts as a signaling molecule, reducing inflammation and oxidative stress.
“BHB acts as a signaling molecule, reducing inflammation and oxidative stress [14, 15]”
From Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study (2018) · cites this paper as [14]
The indexed paper text (labeled Abstract; page unavailable) identifies BHB as an endogenous HDAC inhibitor and reports that it protected mouse kidneys against paraquat-induced oxidative stress. It does not report that BHB reduces inflammation, so that part of the claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBeta-hydroxybutyrate is an endogenous inhibitor of HDACs and can affect gene expression via chromatin modifications and regulate the response to oxidative stress.
“Beta-hydroxybutyrate is an endogenous inhibitor of HDACs and can thereby affect gene expression via chromatin modifications and regulate the response to oxidative stress ((Shimazu et al. 2013)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Shimazu et al. 2013
Administering β-hydroxybutyrate to mice via an intraperitoneal pump enhanced H3K9 and H3K14 acetylation, induced FOXO3A-regulated genes, and increased resistance to oxidative stress.
“By administering β-hydroxybutyrate to laboratory mice via an intraperitoneal pump, Shimazu and colleagues were able to demonstrate enhancement of H3K9 and H3K14 acetylation, induced expression of FOXO3A–regulated genes, and resistance to oxidative stress.”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Shimazu et al., 2013
β-hydroxybutyrate can fuel metabolic adaptation to starvation and help sustain a protective epigenetic state by inhibiting NAD+-independent histone deacetylases.
“These data provide evidence that a distinct metabolite, β-hydroxybutyrate, is able not only to fuel metabolic adaptation to starvation but also to help sustain a protective epigenetic state by inhibiting the activities of NAD+-independent histone deacetylase enzymes.”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Shimazu et al., 2013
β-hydroxybutyrate inhibits many NAD+-independent histone deacetylase enzymes, like sodium butyrate.
“Like sodium butyrate, β-hydroxybutyrate inhibits the activities of many NAD+-independent histone deacetylase enzymes”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Shimazu et al., 2013
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Chen, L., Miao, Z., & Xu, X. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.05.184 · Cited by 92 · see citing works
Varesi, A., Campagnoli, L. I. M., Fahmideh, F., Pierella, E., Romeo, M., Ricevuti, G., Nicoletta, M., Chirumbolo, S., & Pascale, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012289 · Cited by 88 · see citing works
The Influence of Ketogenic Diet on Gut Microbiota: Potential Benefits, Risks and Indications
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Benjamin, D. I., Both, P., Benjamin, J. S., Nutter, C. W., Tan, J. H., Kang, J., Machado, L. A., Klein, J. D. D., de Morree, A., Kim, S., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.04.012 · Cited by 79 · see citing works
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- Authors
- Shimazu, T., Hirschey, M. D., Newman, J., He, W., Shirakawa, K., Le Moan, N., Grueter, C. A., Lim, H., Saunders, L. R., Stevens, R. D., Newgard, C. B., Farese, R. V., de Cabo, R., Ulrich, S., Akassoglou, K., & Verdin, E.
- Affiliations
- Gladstone Institutes (US)
- Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
- Duke University (US)
- Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
- Ithaca College (US)
- Corresponding author
- Verdin, Eric
- ORCID
- Venue
- Science
- Published
- 2013-01-11
- Volume
- 339
- Issue
- 6116
- Pages
- 211-214
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3735349
- OpenAlex
- W2136503478
- Cited by
- 1,777
- References
- 45
- Citations by year
- 2026: 188 · 2025: 176 · 2024: 172 · 2023: 150 · 2022: 190 · 2021: 155 · 2020: 151 · 2019: 133 · 2018: 102 · 2017: 99 · 2016: 92 · 2015: 63 · 2014: 65 · 2013: 40
- FWCI
- 21.58
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Digital Collections - Ithaca College Library (Ithaca College) (submittedVersion, public-domain)
- Funders
- Gladstone Institutes
- National Institute on Aging (T32AG000212)
- National Institute of Allergy and Infectious Diseases (P30AI027763)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056084, P30DK063720, P30DK026743)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- beta-hydroxybutyrate, ketone bodies, histone deacetylase inhibition, histone acetylation, oxidative stress, FOXO3, MT2, caloric restriction, fasting, HDAC1, HDAC2, transcriptional regulation, acetyl-CoA, NAD+, metabolic regulation of gene expression
- MeSH terms
- Forkhead Box Protein O3, Acetylation, Animals, Catalase, Fasting, Histone Deacetylases, Histones, Humans, Kidney, Metallothionein, Mice, Inbred C57BL, Promoter Regions, Genetic, Superoxide Dismutase, Transcription, Genetic, Lipid Peroxidation, Transcriptional Activation, Oxidative Stress, 3-Hydroxybutyric Acid, Caloric Restriction, RNA, Small Interfering, Mice, Forkhead Transcription Factors, Histone Deacetylase Inhibitors, HEK293 Cells
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